Myofibrillar myopathy (MFM) is a genetically heterogeneous group of disorders that involves skeletal and sometimes cardiac muscle and peripheral nerve. The common denominator in each MFM is myofibrillar degradation commencing at the Z-disk. MFM is not uncommon disease, representing the second most common cause of myopathy after the age of 50, but is frequently misdiagnosed or undiagnosed for lack of comprehensive histochemical, immunocytochemical and ultrastructural analysis. As part of a program to nurture the career development of a young neurologist clinician-investigator, we propose to test the postulate that each form of MFM is caused by a defect in a Z-disk related protein, and that mutation analysis of Z-disk related proteins can reveal the molecular basis of MFM. The conceptual framework of this proposal rests on the candidate gene approach, namely that ultrastructural and immunohistochemical clues can point to a candidate gene and protein. In preliminary studies we identified mutations in myotilin and other Z disk related proteins in some MFM kinships, supporting the notion that the ultrastructural clue of early Z-disk disintegration is a valid guide for mutation analysis of MFM. This project is the first step towards unraveling the basis of a relentlessly progressive group of adult disorders, for investigating other inherited neuromuscular disorders by molecular genetic methods and for appropriate genotype phenotype correlations. The proposed project involves close interaction with an established mentor at an institution with a record of excellence in clinically-relevant basic science research. The candidate has already demonstrated potential for independent patient-based laboratory research and, with further training, will develop a successful independent research program including clinically based laboratory research and translational clinical research in neurology.